The Role of PSEN1 Mutations in Alzheimer’s Disease


Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and the sixth leading cause of death in the United States. Despite its prevalence and impact, the exact cause of AD remains unknown.

Existing treatments for AD are primarily focused on targeting the neuropathology associated with the disease, but their effectiveness is limited as they are often administered too late in the disease progression.

To develop more effective treatments, it is crucial to understand the cellular mechanisms underlying AD. Familial AD (fAD), which is caused by autosomal dominant genetic mutations, provides an opportunity to study these mechanisms as it leads to the onset of AD at an earlier age.

The majority of fAD cases are caused by mutations in the Presenilin1 (PSEN1) gene. PSEN1 is a critical component of the γ-secretase complex, which is responsible for cleaving the amyloid precursor protein (APP) and generating amyloid plaques, a hallmark of AD. γ-Secretase also plays a role in the Notch signaling pathway, which is important for cell fate determination during neurodevelopment.

Disruptions in Notch signaling can impact the balance between neural progenitors and post-mitotic neurons, leading to abnormal neurodevelopment. Mutations in PSEN1 can potentially disrupt Notch signaling long before the onset of fAD symptoms.

Studies in mice have shown that embryonic knockout of PSEN1 results in premature neuronal differentiation, reduced neural progenitors, and lethality at birth. Conditional knockout of PSEN1 and its homolog PSEN2 in the forebrain of newborn mice leads to a significant reduction in cortical volume and neuronal number.

These findings highlight the crucial role of PSEN1 in proper neurodevelopment. In humans, over 300 mutations in PSEN1 have been associated with fAD. Among these mutations, the M146L mutation is the most frequently occurring, while the L435F mutation is rare but highly severe, causing widespread Aβ43 cotton wool plaques.

Mutations in PSEN1 can be categorized as either loss-of-function or gain-of-function. Loss-of-function mutations result in reduced γ-secretase activity, while gain-of-function mutations lead to increased activity. For example, the PSEN1 M146L mutation has been shown to increase γ-secretase function, resulting in increased production of Aβ42, a toxic form of amyloid beta, and an elevated Aβ42/40 ratio.

On the other hand, the PSEN1 L435F mutation has been categorized as a loss-of-function mutation in relation to APP processing, as it decreases the production of both Aβ42 and Aβ40 while increasing the Aβ42/40 ratio. However, the L435F mutation has been found to cause a gain-of-function effect in Notch signaling, leading to aberrant neurodevelopment and increased levels of Aβ43.

To study the role of PSEN1 in human neurodevelopment, researchers have turned to human induced pluripotent stem cells (iPSCs). iPSCs can be derived from adult cells and reprogrammed into a pluripotent state, allowing them to differentiate into various cell types, including neurons.

iPSC-derived neurons and neuronal progenitors with different PSEN1 mutations have shown premature neuronal differentiation in vitro, characterized by an increase in neurons and a reduction in Notch intracellular domain (NICD), a key component of Notch signaling. However, neurodevelopment in a human three-dimensional (3D) cellular model has not been extensively studied.

Human iPSC-derived 3D cortical spheroids (hCSs) provide a valuable model to study neurodevelopment in a more physiologically relevant manner. hCSs mimic the structure of the developing human cortex and allow for the investigation of cellular and molecular processes involved in neurodevelopment.

Unlike 2D cultures, hCSs provide a greater opportunity for cell-cell interactions, including Notch signaling, which is crucial for proper neurodevelopment. Additionally, hCSs contain a variety of cell types found in the developing brain, providing a more comprehensive model system.

In a recent study, researchers derived hCSs from iPSC lines carrying the PSEN1 L435F, M146L, or D385A mutations. Isogenic iPSC lines were used, where the only difference between the lines was the specific induced mutation. The researchers found that all three mutations resulted in increased size of the hCSs throughout their development compared to the isogenic control line.

However, the L435F mutation exhibited a distinct morphological change during differentiation. The hCSs carrying the L435F mutation also showed increased neural progenitors and decreased post-mitotic neurons over the lifespan of the hCSs. Notch target genes and NICD levels were increased in hCSs with the L435F mutation, indicating a gain-of-function effect on γ-secretase activity and Notch signaling.

Furthermore, the hCSs with the L435F mutation displayed increased AD-related neuropathology and decreased extracellular neuronal activity.

The findings from this study suggest that specific PSEN1 mutations can have differential effects during neurodevelopment, ultimately leading to the development of fAD later in life. The results also highlight the importance of neuronal development in the pathogenesis of AD. Understanding these mechanisms is crucial for the development of effective interventions that can target AD at an earlier stage, potentially delaying or preventing its onset.

In conclusion, Alzheimer’s disease remains a significant public health challenge with no cure or definitive treatment. The cellular mechanisms underlying the disease are complex and multifaceted. Familial AD, particularly mutations in the PSEN1 gene, provides a valuable model to study the early stages of AD and its impact on neurodevelopment.

Human iPSC-derived 3D models, such as hCSs, offer a powerful tool to investigate the cellular and molecular processes involved in AD pathology. By unraveling the intricate mechanisms underlying AD, researchers hope to develop more effective preventive and therapeutic strategies to combat this devastating disease and improve the lives of those affected by it.


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